Tailored Treatment Suitable for Different Forms of Mastocytosis

Abstract

The present invention relates to a method for a tailored treatment of mastocytosis comprising a) assessing whether or not a c-kit mutation at position 816 is detected in a sample of a patient and b) administering a specific 816 mutant c-kit inhibitor in case a mutation is detected in step a) or an inhibitor displaying efficacy on c-kit wild in case no mutation is detected in step a). The invention is more particularly suited 10 for treating category II, III and IV mastocytosis.

1 . A method for a tailored treatment of mastocytosis comprising
 a) assessing whether or not a c-kit mutation at position 816 is detected in a sample of a patient in need of the treatment; and   b) administering to the patient 816 c-kit mutant inhibitor in case the mutation is detected or an inhibitor displaying efficacy on c-kit wild and/or on juxtamembrane mutated c-kit in case the mutation is not detected.   
     
     
         2 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the mastocytosis is category I mastocytosis, category II mastocytosis, category III mastocytosis, category IV mastocytosis or a symptom associated thereof. 
     
     
         11 . The method of  claim 1 , wherein the mastocytosis is urticaria pigmentosa, diffuse cutaneous mastocytosis, solitary mastocytoma in human, dog mastocytoma, bullous mastocytosis, erythrodermic mastcytosis, teleangiectatic mastocytosis, mastocytosis with an associated hematological disorder, myeloproliferative disorder associated with mastocytosis or mast cell leukemia. 
     
     
         12 . The method of  claim 1 , wherein the mastocytosis is category IV mastocytosis and wherein the method further comprises administering to the patient a compound selected from a group consisting of 2-Chloro-2′-desoxyadenosine and analogs thereof. 
     
     
         13 . A method of treating Category II, III or IV mastocytosis in a patient having a c-kit mutation at position  816 , said method comprising
 administering to the patient a 816 c-kit mutant inhibitor.   
     
     
         14 . The method of  claim 13 , wherein the 816 c-kit mutant inhibitor is a compound of formula III 
       
         
           
           
               
               
           
         
         wherein R 1  is 
         a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with a least one heteroatom or bearing a pendant basic nitrogen functionality; 
         b) an aryl or heteroaryl group optionally substituted with alkyl or aryl group, optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; 
         c) a sulfonyl or a —SO 2 R group wherein R is an alkyl, aryl or heteroaryl substituted with a heteroatom or bearing a pendant basic nitrogen functionality; or 
         d) a —CO—NH—R, —CO—R, —CO—OR or a —CO—NRR′, wherein R and R′ are independently selected from a group consisting of H, aryl group optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, heteroaryl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, alkyl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, cycloalkyl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; 
         R 2  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
         R 3  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
         R 4  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
         R 5  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
         R 6  is 
         (i) an aryl group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
         (ii) a heteroaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
         (iii) a five-member aromatic heterocyclic group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; or 
         (iv) H, I, F, Br, Cl, NH 2 , NO 2  or SO 2 ; 
         and R 7  is 
         (i) an aryl group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
         (ii) a heteroaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
         (iii) a five-member aromatic heterocyclic group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; or 
         (iv) H, I, F, Br, Cl, NH 2 , NO 2  or SO 2 . 
       
     
     
         15 . A method of treating Category I, II, III or IV mastocytosis in a patient not bearing a c-kit mutation at position 816, said method comprising
 administering to the patient an inhibitor displaying efficacy on c-kit wild and/or on juxtamembrane mutated c-kit.   
     
     
         16 . The method of  claim 15 , wherein the inhibitor is a compound of formula III: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is
 a) a linear or branched alkyl group containing from 1 to 10 carbon atoms optionally substituted with a least one heteroatom or bearing a pendant basic nitrogen functionality; 
 b) an aryl or heteroaryl group optionally substituted with alkyl or aryl group, optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; 
 c) a sulfonyl or a —SO 2 R group wherein R is an alkyl, aryl or heteroaryl substituted with a heteroatom or bearing a pendant basic nitrogen functionality; or 
 d) a —CO—NH—R, —CO—R, —CO—OR or a —CO—NRR′, wherein R and R 1  are independently selected from a group consisting of H, aryl group optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, heteroaryl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, alkyl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality, cycloalkyl optionally substituted with at least one heteroatom or bearing a pendant basic nitrogen functionality; 
 R 2  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
 R 3  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
 R 4  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
 R 5  is hydrogen, halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl or alkoxy; 
 R 6  is 
 (i) an aryl group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
 (ii) a heteroaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
 (iii) a five-member aromatic heterocyclic group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; or 
 (iv) H, I, F, Br, Cl, NH 2 , NO 2  or SO 2 ; 
 and R 7  is 
 (i) an aryl group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
 (ii) a heteroaryl group optionally substituted with one or more substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; 
 (iii) a five-member aromatic heterocyclic group optionally substituted with one or substituents selected from the group consisting of halogen, a linear or branched alkyl group containing from 1 to 10 carbon atoms, trifluoromethyl and alkoxy; or 
 (iv) H, I, F, Br, Cl, NH 2 , NO 2  or SO 2 . 
 
     
     
         17 . The method of  claim 15 , wherein the inhibitor is a N-phenyl-2-pyrimidine-amine compound of formula II 
       
         
           
           
               
               
           
         
         wherein R1, R2 and R3 are each independently selected from the group consisting of H, F, Cl, Br, I, C1-C5 alkyl group, cyclic group and heterocyclic group, 
         wherein R4, R5 and R6 are each independently selected from H, F, Cl, Br, I, and C1-C5 alkyl group, 
         and wherein R7 is phenyl group substituted with at least one substituent, said substituent has at least one basic site. 
       
     
     
         18 . A method of diagnosing mastocytosis in an individual, said method comprising
 a) reversing transcription of a RNA sample from a skin of the individual using oligo dT primers and random primers to obtain a cDNA;   b) amplifying the cDNA using primers   
       
         
           
                 
                 
                 
                 
               
                     
                   U2 
                     
                     
                 
                     
                   (5′ GGATGACGAGTTGGCCCTAGA 3′) 
                   (SEQ ID NO 1) 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   L1 
                 
                     
                   (5′ GTAGAACTTAGAATCGACCGGCA 3′), 
                   (SEQ ID NO 2) 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   5′ ATCCTCCTTACTCATGGTCGGATC 3′ 
                   (SEQ ID NO 5) 
                 
                     
                     
                 
                     
                   5′ CGACCGGCATTCCAGGATAG 3′ 
                   (SEQ ID NO 6) 
                 
             
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         c) detecting the presence or the absence of the c-kit of c-DNA corresponding to 816 position of the c-kit.